Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

Lakshmi, Sowmya P.; Reddy, Arava Leela Mohana; Zhang, Yingze; Sciurba, Frank C.; Mallampalli, Rama K.; Duncan, Steven R.; Reddy, Raju C.

doi:10.1074/jbc.m113.536805

Cited by 64 publications

(63 citation statements)

References 34 publications

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“…The density of the bands was evaluated regulates genes that are implicated in adipocyte differentiation, lipid and glucose metabolism, and insulin sensitivity. PPAR ␥ also plays a central role in dampening infl ammation via its inhibitory activity on expression of the proinfl ammatory mediators (19)(20)(21). Notably, treatment of rats with the ligands of PPAR ␥ can signifi cantly protect the brain from ischemic insult by acting against infl ammatory responses (22)(23)(24)(25)(26)(27).…”

Section: Western Blot Analysismentioning

confidence: 99%

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

Sun

Han

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org to form a series of biologically active lipid mediators ( 1, 2 ). In the CNS, 12/15-LOX expression has been described throughout the cerebrum, basal ganglia, and hippocampus ( 3, 4 ). Arachidonic acid (AA) is an important component of membrane lipids that can activate several signaling pathways directly by itself or by its metabolites ( 5 ). In nervous tissue, the major enzymatic route for AA metabolism is the 12/15-LOX pathway, and the principal metabolites are 12(S)-HETE and 15(S)-HETE ( 3, 4, 6, 7 ). The biological signifi cance of these metabolites of AA is that they have been proposed to play roles as second messengers in synaptic transmission and they are thought to be involved in learning and memory processes ( 8 ). In addition, 12(S)-HETE is known to act as an inhibitory neuromodulator by reducing voltage-sensitive calcium channel activity ( 9 ) and attenuating glutamate release and affi nity to its receptors ( 10-12 ).Brain ischemia triggers the massive release of free fatty acids from membrane stores, such as AA and DHA, and then the accumulation of lipid peroxides. 12/15-LOX is thought to be damaging because of its lipid-oxidizing properties, and the detrimental effects of 12/15-LOX have been documented by demonstrating the protection in the ischemic brain through 12/15-LOX inhibition or gene deletion ( 13-15 ). Several metabolites of 12/15-LOX, however, have neuroprotective and anti-infl ammatory qualities during brain ischemia. For example, 12/15-LOX metabolites derived from DHA and other -3 fatty acids inhibit cerebral ischemia-induced injury (16)(17)(18). This suggests 12/15-LOX and its metabolites may differ in their effects following cerebral ischemia.PPAR ␥ is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. This work was supported by grants from the National Natural Science Foundation of China (number 81070968 to L.S. and number 81401023 to Y-W.X.) and from the Tianjin Municipal Science and Technology Commission (number 13ZCZDSY01900 to Y.C.). The authors declare no confl icts of interest. Manuscript received 15 July 2014 and in revised form 12(S)-and 15(S)-HETE activate PPAR ␥ in ischemic brain 503animals survived the MCAO surgical procedure. Rats that did not demonstrate neurological defi cits during 90 min MCAO were excluded from further study. Animals dying prematurely during the reperfusion period or having subarachnoid hemorrhage at postmortem examination were also excluded. Measurements derived from these animals were not included in the present study. Drug treatmentEicosanoids, 12(S)-HETE and 15(S)-HETE, were products of Cayman Chemical (Ann Arbor, MI) and given 30 min before the onset of MCAO by icv injection. 12(S)-and 15(S)-HETE, supplied in ethanol at 1 mg/ml, were air-dried under a stream of nitrogen and dissolved in a 30% DMSO and 70% isotonic saline solution ( 35 ). Animals received either vehicle (30% DMSO-0.9% saline) or a single dose of 12(S)-or 15(S)-HETE at 10, 15, or 20 g ( ‫...

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Section: Western Blot Analysismentioning

confidence: 99%

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

Sun

Han

et al. 2015

Journal of Lipid Research

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“…Treating epithelial cells with PPARγ agonists suppresses CSE-induced increase of inflammatory cytokines, and reverses activation of NF-B by promoting direct inhibitory binding of PPARγ to NF-B. In pulmonary epithelial cells, down-regulation of PPARγ by cigarette smoke promotes inflammatory processes and diminishes glucocorticoid responsiveness, which favors the COPD pathogenesis [163].…”

Section: Chronic Obstructive Pulmonary Disease (Copd) [163]mentioning

confidence: 99%

“…PPARγ has been shown to be a negative regulator of profibrotic signal-induced collagen synthesis and to blunt fibrosis in various pathological circumstances [6,7,93,98,100,103,[122][123][124][161][162][163]. PPARγ ligands diminish fibrotic effects.…”

Section: Concerted Actions Of Tgf-β Wnt Smads and Yap/taz Pathways mentioning

confidence: 99%

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

Lecarpentier¹,

Schussler

Claes

et al. 2017

Nuclear Receptor Research

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Abstract. Myofibroblasts are non-muscular contractile cells that occur physiologically in organs such as in stem villi of the human placenta during normal pregnancies. They have the ability to contract and relax in response to changes in the volume of the intervillous chamber. Myofibroblasts are also found in many pathological states, and are involved in wound healing and fibrosis processes in several organs such as liver, lung, kidney, and heart. During fibrosis, the contractile phenomenon is a relaxation-free mechanism, associated with the synthesis of collagen in the extracellular matrix (ECM), which leads to irreversible fibrosis, tissue retraction and finally apoptosis of the myofibroblasts. The molecular motor of myofibroblasts is the non-muscle myosin type II (NMII). Differentiation of fibroblasts into myofibroblast is largely regulated by the Transforming Growth Factor-β1 (TGF-β1). This system regulates the canonical WNT/β-catenin pathway in a positive manner and PPARγ in a negative manner. WNT/β-catenin promotes fibrosis while PPARγ prevents fibrosis. This review focuses on the contractile properties of myofibroblasts and on the TGF-β1 conductor which regulates the antagonism between PPARγ and the canonical WNT/β-catenin pathway.

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“…In preclinical studies peroxisome proliferator-activated receptor-γ (PPARγ) agonists exert anti-inflammatory effects potentially relevant to the treatment of inflammatory airway diseases including asthma and COPD Belvisi and Hele, 2008;Seidel et al 2012;Stephen et al 2013;Bourke et al 2014;Lakshmi et al 2014;Lea et al 2014;Donovan et al 2015]. For example, PPARγ agonists reduce eosinophilic and neutrophilic lung infiltration in experimental animal models exposed to allergen or tobacco smoke [Bauer et al 2010;Lea et al 2014;Zhao et al 2014;Morissette et al 2015].…”

Section: Pparγ Agonistmentioning

confidence: 99%

Novel approaches to the management of noneosinophilic asthma

Thomson

2016

Ther Adv Respir Dis

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Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

Cited by 64 publications

References 34 publications

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

12/15-Lipoxygenase metabolites of arachidonic acid activate PPARγ: a possible neuroprotective effect in ischemic brain

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

Novel approaches to the management of noneosinophilic asthma

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